Calcium signaling and postsynaptic density dynamics: the roles of calmodulin in synaptic protein regulation

Calcium signaling in neuronal cells is the principal mechanism underlying learning and synaptic plasticity, whereas the postsynaptic density (PSD) is an important center where calcium-dependent processes are organized and regulated. This review explores the roles of calmodulin (CaM) in facilitating calcium-dependent modulation of the activities of synaptic proteins in the PSD. We focus on the molecular processes through which CaM interacts with calcium signals to regulate the function, localization, and interactions of central synaptic proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII), membrane-associated guanylate kinases (MAGUKs), and N-methyl-D-aspartate (NMDA) receptors. We aim to summarize recent advances in structural, biochemical, and imaging studies of how CaM's structural flexibility, calcium binding kinetics, and protein-protein interactions uncover complex regulatory loops that allow exquisite temporal and spatial control over synaptic efficacy. Additionally, research progress on how disruptions of CaM-mediated signaling pathways are linked to neurological diseases, which may be conducive to new potential therapeutic interventions, is discussed.